Abuse resistant drugs, method of use and method of making

ABSTRACT

An abuse resistant oral pharmaceutical composition, comprising: a barrier layer, comprising a first polymer; a diffusion layer, comprising a second polymer, substantially covering the barrier layer, wherein the diffusion layer is bonded to the barrier layer and comprises a drug that is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the gastrointestinal (GI) tract; and optionally an expansion layer comprising an expandable polymer, wherein the expansion layer is substantially covered by the barrier layer. Methods of making the same and methods of using the same are also provided.

This application claims priority from U.S. Provisional Application Ser.No. 60/955,584 filed Aug. 13, 2007, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions, and specifically relates to compositions that are designedto reduce the potential for improper administration of medications andtheir use in a non-indicated or non-prescribed manner. The presentinvention can comprise any drug, especially medications that are subjectto abuse. More specifically, it pertains to pain medications,medications to reduce or eliminate anxiety attack (psychotherapeuticdrugs), stimulants and sleeping pills. With these general type drugsthere is the potential of abuse that may result in drug overdose,addiction, suboptimal efficacy, and/or death.

In particular, the present invention relates to an abuse resistantcomposition (for, e.g., pain medication, anxiety attack medication,sleeping medication or stimulants), having, but not limited to, adiffusion layer and a barrier layer; use of such a composition in adosage form to treat diseases or conditions; and a method of making anabuse deterrent composition having a diffusion layer and a barrierlayer. In some embodiments, the composition also comprises an expansionlayer.

Opioid agonists are substances that act by attaching to specificproteins called opioid receptors, which are found in the brain, spinalcord, and gastrointestinal tract. When these drugs attach to certainopioid receptors in the brain and spinal cord they can effectively blockthe transmission of pain messages to the brain. Opioid analgesics suchas oxycodone, morphine, oxymorphone, hydrocodone and hydromorphone aresuccessful and therapeutically useful pain medications. Unfortunately,they also pose a severe threat for willful abuse due to their ability toalter mood and/or cause a sense of euphoria (a “high”). Currentlyavailable sustained release formulations of such drugs, which contain arelatively large amount of drug substance meant to be released from theformulation over an extended time period, are particularly attractive toabusers since the sustained release action can be destroyed by crushingor grinding the formulation. The resulting material (i.e., the crushedformulation) can no longer control the release of drug. Depending on thedrug substance, abusers can then (1) snort the material, (2) swallow thematerial or (3) dissolve the material in water or alcohol andsubsequently inject it intravenously. The dose of drug contained in theformulation is thus absorbed immediately through the nasal or GI mucosa(for snorting or swallowing, respectively) or is administered in a bolusto the systemic circulation (for IV injection).

These abuse methods result in the rapid bioavailability of relativelyhigh doses of drug contained in a single tablet or capsule, giving theabuser a “high.” The sense of euphoria, or “high,” is highly correlatedwith the peak serum concentration of the drug substance (Cmax). Althoughsuch a high serum concentration can be obtained from taking severalimmediate release or sustained release tablets at once, abusers aredeterred from doing so because multiple tablets are harder to come byand, maybe more importantly, the very high dose associated with takingseveral tablets at once is associated with an severely increased risk ofoverdose (typically a function of high serum levels of the drugsubstance over prolonged periods of time; resulting in a high area underthe curve: the integral of the serum concentration over time, also knownby the acronym “AUC”). In order to reduce the risk of overdose, thetypical abuser will prefer to obtain a high peak serum concentrationfrom a single tablet or capsule. In the scientific terminology of apharmacologist, the typical abuser appears to maximize Cmax whileminimizing AUC, or alternatively, to maximize the Cmax/AUC ratio.

In some cases, abusers consume alcohol with immediate and/or extendedrelease formulations to reach a “high” more quickly. Abusers sometimesplace the formulation in water or alcohol, in order to extract the drugin an accelerated fashion. The coadministration of these liquids isknown to sometimes decrease the time after drug administration in whichthe peak plasma concentration and Cmax are reached. Sometimes abusersplace the formulation into other solvents such as freon, methylenechloride, ethanol, and acetone, in order to extract the drug, which canthen be injected. Another technique used by abusers to extract drug froma dosage form such as a tablet is wiping the coating off of the tablet,crushing the tablet into a fine powder, placing the powder into sterilewater, and then drawing the liquid into a syringe. In addition, thedosage form can be generally physically compromised by crushing,grinding, and chewing.

Since relatively simple methods (crushing, grinding, chewing and/ordissolution in water or alcohol) can be used to transform a singleextended release tablet or capsule formulation into an abusable form,these conventional dosage forms provide virtually no deterrent to apotential abuser.

The FDA recently strengthened the warnings and precautions sections inthe labeling of OXYCONTIN® (oxycodone HCl controlled-release) Tablets, anarcotic drug approved for the treatment of moderate to severe pain,because of continuing reports of abuse and diversion. OXYCONTIN®contains oxycodone HCl (available in 10, 20, 40, 80, and 160 mgstrengths), an opioid agonist with an addiction potential similar tothat of morphine. OXYCONTIN® is supplied in a controlled-release dosageform and is intended to provide up to 12 hours of relief from moderateto severe pain. The FDA warning specifically states that the tablet mustbe taken whole and only by mouth. When the tablet is chewed or crushedand its contents are swallowed, snorted into the nostrils or dissolvedand subsequently injected intravenously, the controlled releasemechanism is destroyed and a dangerous dose of oxycodone becomesbioavailable, which is potentially lethal to users of this product, inparticular first time users.

In recent years, there have been numerous reports of oxycodone diversionand abuse in several states. For example, DEA's Office of DiversionControl reported 700 OXYCONTIN® thefts in the U.S. between January 2000and June 2001. Some of these reported cases have been associated withserious consequences, including death.

Oxycodone is a controlled substance in Schedule II of the ControlledSubstances Act (CSA), which is administered by the Drug EnforcementAdministration (DEA). Despite the fact that Schedule II provides themaximum amount of control possible under the CSA for approved drugproducts, in practice it is difficult for law enforcement agencies tocontrol the diversion or misuse of legitimate prescriptions. Althoughabuse, misuse, and diversion are potential problems for all opioids,including oxycodone, opioids are a very important part of the medicalarmamentarium for the management of pain when used appropriately underthe careful supervision of a physician. Currently available formulationsfor such drugs are designed for oral administration but do not includemechanisms to prevent or retard improper methods of administration suchas chewing, injection and snorting. This represents a serious problemgiven the large number of legitimate prescriptions written in the U.S.;for example, the medical use of opioids within the U.S. increased 400%from 1996 to 2000.

The problems with abuse are significant and longstanding, and efforts todesign new abuse resistant or abuse deterrent formulations have beenlargely unsuccessful. U.S. Pat. No. 3,980,766 describes theincorporation of an ingestible solid which causes a rapid increase inviscosity (gelling) upon concentration of an aqueous solution thereof.U.S. Pat. No. 4,070,494 describes the incorporation of a non-toxic,water gelable material in an amount sufficient to render the drugresistant to aqueous extraction, thus retarding the release of the drugsubstance. U.S. Pat. No. 6,309,668 describes a tablet for oraladministration containing two or more layers comprising one or moredrugs and one or more gelling agents within separate layers of thetablet. The examples in this patent all describe conventional immediaterelease formulations and the resulting tablets form a gel when combinedwith the volume of water necessary to dissolve the drug; thisformulation thus reduces the extractability of the drug from the tablet.It should be noted that although these compositions may preclude abuseby injections, this approach would fail to prevent abuse by crushing andswallowing or snorting the formulation, which are commonly reportedmethods of abuse associated with OXYCONTIN®.

U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 describe oral dosageforms including a combination of an orally active opioid agonist and anorally active opioid antagonist in a ratio that, when delivered orally,is analgesically effective but that is aversive in a physicallydependent subject. While such a formulation may be successful indeterring abuse, it also has the potential to produce adverse effects inlegitimate patients.

U.S. Patent Application Publication No. 2007/0066537 discloses an abuseresistant opioid wherein the opioid is bound to niacin, biotin orpeptide.

U.S. Patent Application Publication No. 2006/0104909 discloses apharmaceutical composition comprising an opioid and a tamper-resistantmatrix comprising one or more tenacious cross-linked polymers that arecapable of bonding with the opioid such that the opioid is substantiallyincapable of immediate release from the polymer. A further preferredaspect uses a water insoluble matrix material comprising a pHinsensitive material such as ethylcellulose, cellulose acetate, vinylacetate/vinyl chloride copolymers, acrylate/methacrylate copolymers,polyethylene oxide, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, triglycerides, hydrogenatedvegetable oils, triglyceride polyalkoxyalkylesters, fats, waxes andwater insoluble partially-degraded proteins. The surface coatingmaterial comprises a hydrophobic polymer such as a pharmaceuticallyacceptable acrylic polymer such as acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid), polymethacrylic acid, methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methacrylic acid anhydride), methylmethacrylate, polymethacrylate, polyacrylamide and glycidyl methacrylatecopolymers. In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inNF XVII as fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups.

U.S. Patent Application Publication No. 2005/0281748 discloses an opioidbound to a lipid or fatty acid to produce an abuse resistant drug.

It is an object of the present invention to provide a pharmaceuticalcomposition that significantly reduces the potential for improperadministration or use of drugs but which, when administered as directed,is capable of delivering a therapeutically effective dose. Inparticular, the present invention addresses the need for a drug productwhich, compared to conventional formulations, decreases the intensity,quality, frequency and rate of occurrence of the “euphoria” effect whichcan occur with improper administration.

SUMMARY OF THE INVENTION

The present invention relates to an abuse resistant oral pharmaceuticalcomposition, comprising: a barrier layer, comprising a first polymer;and a diffusion layer, comprising a second polymer, substantiallycovering the barrier layer, wherein the diffusion layer is bonded to thebarrier layer and comprises a drug that is substantially homogeneouslydistributed within the second polymer and diffuses from the diffusionlayer within the gastrointestinal (GI) tract. The pharmaceuticalcomposition may optionally comprise an expansion layer comprising anexpandable polymer and wherein the barrier layer substantially coversthe expansion layer.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition in configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the rate of drug released from the composition withina time period selected from the group consisting of 2 hours, 4 hours, 8hours and 16 hours is substantially the same or lower than the rate ofdrug released when the pharmaceutical composition is administered in anintact form.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the amount of drug released from the compositionwithin a time period selected from the group consisting of 2 hours, 4hours, 8 hours and 16 hours, is substantially the same or lower,preferably less than 20%, more preferably less than 30%, and mostpreferably less than 40%, than the amount of drug released when thepharmaceutical composition is administered in an intact form. In thecontext of this application, the phrase “substantially the same” meanswithin (+/−) 30%, preferably within (+/−) 20%, and more preferablywithin (+/−) 10%.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition in configured such that when thepharmaceutical composition is contacted with an alcohol or consumed withan alcohol, the rate of drug released from the composition within a timeperiod selected from the group consisting of 2 hours, 4 hours, 8 hoursand 16 hours, is substantially the same or lower, preferably less than40%, more preferably less than 30%, and most preferably less than 20%,than the rate of drug released when the pharmaceutical composition isadministered without an alcohol.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least50% of the amount of drug is released after 8 hours and when thepharmaceutical composition is administered in physically compromisedform no more than 40%, preferably no more than 30%, of the amount ofdrug is released after 1 hour.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least90% of the amount of drug is released after 1 hour and when thepharmaceutical composition is administered in physically compromisedform no more than 75% of the amount of drug is released after 1 hour.

The present invention also relates to a method of making an abuseresistant oral pharmaceutical composition, comprising: forming a barrierlayer, wherein the barrier layer comprises a first polymer; and applyinga diffusion layer over the barrier layer to substantially cover thebarrier layer, wherein the diffusion layer comprises a second polymerand a drug that is homogeneously distributed within the second polymer;and bonding the diffusion layer to the barrier layer, preferably byphysical bonding.

The present invention also relates to a method of making an abuseresistant oral pharmaceutical composition, comprising: forming anexpansion layer comprising an expandable polymer; applying a barrierlayer over the expansion layer to substantially cover the expansionlayer, wherein the barrier layer comprises a first polymer; and applyinga diffusion layer over the barrier layer to substantially cover thebarrier layer, wherein the diffusion layer comprises a second polymerand a drug that is homogeneously distributed within the second polymer;and bonding the diffusion layer to the barrier layer, preferably byphysical bonding. In some embodiments, the barrier layer can be appliedonto the expansion layer by spraying or dry coating.

The present invention also relates to a method of treating a condition,comprising administering to a patient in need thereof the pharmaceuticalcomposition of the invention.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the intensity of the euphoria is substantially thesame or lower than the intensity of the euphoria achieved afteradministration of a physically compromised bioequivalent composition notcomprising means for deterring abuse.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of percent release rate versus time of a tablet madeaccording to Example 31 when taken properly (intact) as compared to aground form of the same tablet formulation.

FIG. 2 is a graph of percent release rate versus time of a ground tabletof OXYCONTIN® versus a ground tablet of the formulation of Example 31.

FIG. 3 is an in vivo simulation showing features of the invention,prepared utilizing the Microsoft Excel software program. Currentlymarketed immediate or extended release tablets would exhibit Cmax-1 asshown after grinding the tablets and subsequently snorting the groundpowder. The same tablets when ingested intact would show Cmax-2, as therate of absorption will be delayed due to physiological factors in theGI tract. A bioequivalent tablet formulation of the invention would showthe same profile as the Cmax-2 curve. However, the tablets of thecurrent invention when ground and snorted would show the lower Cmax-3.

FIG. 4 is a graph of percent release rate versus time of a tablet madeaccording to Example 31 when taken properly (intact) as compared to a“cut form” of the same tablet formulation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The concept behind the present invention of an abuse resistantpharmaceutical composition is to provide the necessary amount of a drugto the patient to accomplish the pharmaceutical effect (such as painrelief), while decreasing the ability of a potential abuser to alter thecomposition in order to experience a “high” or to induce rapid death.Drugs which are typically abused, and therefore are suitable for thepresent invention, include pain medications, such as opioids, anxietyattack medications, sleeping medication, and stimulants, among others.

The abuse deterrent composition of the invention can retard, or at leastnot increase significantly, the release of the drug substance from adosage form when the physical integrity of the dosage form containingthe composition is compromised and the resulting formulation issubsequently snorted, injected, or swallowed. The composition is“physically compromised” when it is in a form other than an intact form.This can be achieved by various means such as by chewing, chopping,grinding, crushing, or placing into solvents, such as those containingan alcohol (e.g., ethyl alcohol) and/or water. The composition of theinvention thus provides a deterrent to common methods of improperadministration, including intravenous injection of the drug dissolved insolvent, and nasal or oral administration of the crushed formulation, asthe drug will not be immediately and rapidly released from theformulation and as the actual amount of drug release can be decreased ascompared to an intact formulation. When administered as directed, thedrug substance is released more gradually from the composition withinthe gastrointestinal (GI) tract, preferably by dissolution and/ordiffusion mechanisms.

According to one embodiment, the abuse resistant pharmaceuticalcomposition of the present invention comprises: a barrier layer,comprising a first polymer; and a diffusion layer, comprising a secondpolymer, substantially covering the barrier layer, wherein the diffusionlayer is bonded to the barrier layer and comprises a drug that issubstantially homogeneously distributed within the second polymer anddiffuses from the diffusion layer within the gastrointestinal tract. Thepharmaceutical composition optionally comprises an expansion layercomprising an expandable polymer. In embodiments wherein thepharmaceutical composition comprises an expansion layer, the barrierlayer substantially covers the expansion layer.

The abuse deterrent composition of the invention can comprise either orboth extended release formulations, with a typical in vivo or in vitroslow release of drug over a period of about 6 to about 24 hours,preferably at least 80% of the drug released at about 12 to about 24hours, as well as immediate release formulations, preferably with arelease of at least 80%, more preferably at least 90% and mostpreferably at least 95%, of the drug in one hour, designed for oraladministration.

The abuse resistant oral pharmaceutical composition can be in anypharmaceutical dosage form, including, but not limited to a tablet, acapsule, a micro tablet, granules, pellets, a lollipop, a lozenge and acoated capsule. In preferred embodiments, the abuse resistant oralpharmaceutical composition is in a tablet dosage form.

In embodiments where the abuse resistant oral pharmaceutical compositioncomprises the optional expansion layer, the expansion layer is theinnermost of the three layers of the drug composition. The expansionlayer is preferably an inert layer, which does not contain any drug, andit comprises an expandable polymer. The expansion layer preferably has athickness of about 0.5 to 15 mm, more preferably about 2 to 12 mm, andmost preferably about 4 to 10 mm. The thickness of the expansion layeris preferably about 5 to 95%, more preferably about 40% to 95%, and mostpreferably about 50% to 90% of the thickness of the tablet.

In some embodiments, when the expandable polymer of the optionalexpansion layer is exposed to liquids, preferably liquids comprisingwater and/or an alcohol such as ethyl alcohol, the expandable polymerabsorbs the liquid, and preferably expands and/or forms a gel. It ispreferably a hydrophilic polymer, most preferably a hydrophilic polymerthat swells upon contact with liquids and/or gels. In a preferred form,when the expansion layer is exposed to a liquid after the abusedeterrent composition is physically compromised and fragments of thecomposition containing the expansion layer are formed, the expandablepolymer absorbs at least a portion of the liquid and forms a gel.Preferably the gel further retards release of the drug from thediffusion layer. Further, the increased viscosity may make it difficultfor an abuser to draw up the formulation into a syringe for injection.The expansion layer preferably comprises a polymer present in the rangeof 5 to 90% by weight, based on the total weight of the dosage form.

Typical agents employed in the expansion layer include, but are notlimited to methylcellulose, sodium carboxymethylcellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose, alginic acid,polyacrylic acid, and tragacanth, or a combination of two or more ofthese substances. Most preferred are hydroxypropyl methylcellulose,which is sometimes marketed under the tradename METHOCEL® andpolyacrylic acid, which is sometimes marketed under the tradenameCARBOPOL®.

The expansion layer may also include a disintegrant such ascroscarmellose sodium or sodium starch glycolate, to help assure theexpansion layer quickly disperses in a liquid. Additional ingredientswhich may be present in the expansion layer include, but are not limitedto fillers, dyes, lubricants or water permeation enhancers such assodium chloride. The use of highly soluble polymers, disintegrants orcombinations thereof is generally known in the pharmaceutical arts, andas would be understood to one skilled in the art, any suitable highlysoluble polymer or disintegrant or equivalent substances may be used inconjunction with the present invention and embodiments thereof.

The barrier layer is interior to the diffusion layer. In someembodiments wherein the pharmaceutical composition comprises anexpansion layer, the expansion layer is the innermost of the threelayers and the barrier layer substantially covers the expansion layer.Substantial covering of the expansion layer means that more that 80%,more preferably more than 90%, and most preferably more than 95% of theexpansion layer is covered by the barrier layer. 100% coverage is mostsuitable.

The barrier layer preferably has a thickness of about 0.1 to 2.5 mm,more preferably about 0.2 to 2.0 mm, and most preferably about 0.5 to1.5 mm. The thickness of the barrier layer is preferably about 5 to 50%,more preferably about 8 to 30%, and most preferably about 10 to 25% ofthe total thickness of the composition.

The barrier layer serves a number of functions. For example, the barrierlayer acts as barrier between the diffusion layer and the expansionlayer, decreasing the amount of liquid that can enter into the expansionlayer when the dosage form is in an intact form. Further, the barrierlayer acts to improve the mechanical strength of the composition.

The barrier layer comprises a polymer. Typical barrier layer polymersinclude, but are not limited to, polyacrylates and the copolymersthereof (such as those marked under the tradename EUDRAGIT® NE 30 D),EUDRAGIT® FS 30 D, EUDRAGIT® RS 30 D, SURELEASE® from COLORCON®,AQUACOAT® from FMC® and mixtures of EUDRAGIT® NE 30 D and AQUACOAT®,polyethylene glycol, polyethylene oxides, polyethylenes, polypropylenes,polyvinyl chlorides, polycarbonates, polystyrenes, and the like. Thepreferred polymers of the barrier layer are polyacrylate andpolyethylene glycol and in particular, a polyacrylate dispersion. Inembodiments wherein the pharmaceutical composition comprises anexpansion layer, the barrier layer may also contain an adhesion agent tohelp it adhere to the expansion layer. The use of polymers resistant tobiodegradation, adhesion agents or combinations thereof is generallyknown in the pharmaceutical arts, and as would be understood to oneskilled in the art, any suitable bioresistant polymer or adhesionenhancing agent may be used in conjunction with the present inventionand embodiments thereof.

Preferably, when a dosage form containing the abuse deterrentpharmaceutical composition of the present invention is administered to asubject in the intact form, the barrier layer polymer does notsubstantially dissolve in the GI tract, mucous membranes, blood vesselsor lungs. Rather, the barrier layer polymer passes through the body in asubstantially undissolved form. “Substantially undissolved” means thatless than 30%, more preferably less than 20% and most preferably lessthan 10% of the polymer is dissolved.

The diffusion layer substantially covers the barrier layer. Substantialcovering of the barrier layer means that more that 80%, more preferablymore than 90%, and most preferably more than 95% of the expansion layeris covered by the barrier layer. 100% coverage is most suitable.

The diffusion layer comprises a polymer and a drug, preferably a drugwhich is substantially homogeneously distributed in the polymer.“Substantially homogeneously distributed” means that more that 80%, morepreferably more than 90%, and most preferably more than 95% of the drugis homogeneously distributed. The polymer and drug dispersion of thediffusion layer is applied and bonded to the barrier layer.

The diffusion layer preferably is a thin layer with a large surface arearelative to the thickness of the layer. The diffusion layer preferablyhas a thickness of about 0.1 to 1.0 mm, more preferably about 0.15 to0.7 mm, and most preferably about 0.2 to 0.4 mm. The thickness of thediffusion layer is preferably about 1 to 30%, more preferably about 2 to20%, and most preferably about 3 to 10% of the thickness of the tablet.In the preferred embodiments of this invention, the diffusion layer isrelatively thin as compared to the surface area of the diffusion layer.

In some preferred embodiments, one or more of the layers can contain dyewhich, when in contact with liquid or mouth saliva, will produce a stainor color. This could aid in abuse resistant characteristics of thetablets of the present invention. Examples of dyes include, but are notlimited to, FD&C Red #3, FD&C Red # 28 and FD&C Blue # 1.

The drug incorporated in the pharmaceutical compositions of theinvention can be any drug, or any combinations of two or more drugs.However, typically, the drug or drugs will be one that is often abused,such as central nervous system stimulants and depressants. Examples ofcentral nervous system stimulants include, but are not limitedamphetamines and agents such as cocaine. Examples of central nervousdepressants include, but are not limited to opioids, barbiturates,benzodiazepines, and other anxiety and sleep medications. Examples ofcombinations of two drugs include oxycodone and morphine.

Examples of opioids include, but are not limited to the following:alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, and tramadol. Anyopioid or pharmaceutically acceptable salt or ester thereof may be usedin the abuse deterrent composition. Preferred opioids include fentanyl,sufentanil, carfentanil, lofentanil, alfentanil, hydromorphone,oxycodone, morphine, hydroxycodone, propoxyphene, pentazocine,methadone, tilidine, butorphanol, buprenorphine, levorphanol, codeine,oxymorphone, meperidine, and dihydrocodeinone. More preferred opioidsinclude oxycodone, hydrocodone, codeine, morphine, oxymorphone andhydromorphone, and pharmaceutically acceptable salts and esters thereof.The most particularly preferred opioids are oxycodone and morphine andpharmaceutically acceptable salts thereof.

Examples of barbiturates include, but are not limited to mephobarbital(which is sometimes marketed under the tradename MEBARAL®) andpentobarbital sodium (which is sometimes marketed under the tradenameNEMBUTAL® Barbiturates are often prescribed to treat anxiety, tension,and sleep disorders.

Examples of benzodiazepines and benzodiazepine derivatives include, butare not limited to diazepam (sometimes marketed under the tradenameVALIUM®), alprazolam (sometimes marketed under the tradename XANAX®),triazolam (HALCION®), and estazolam (PROSOM®). Benzodiazepines are oftenprescribed to treat anxiety, acute stress reactions, and panic attacks.

An example of another CNS depressant is zaleplon, which is sometimesmarked under the tradename SONATA®.

Although the various classes of CNS depressants work differently, theyall can produce a beneficial drowsy or calming effect in individualssuffering from such conditions as sleep disorders and anxiety. However,if one uses these drugs over a long period of time, the body can developtolerance, and larger doses may be needed to achieve the initialeffects. In addition, continued use can lead to physical dependence and,when use is reduced or stopped, withdrawal symptoms. Both barbituratesand benzodiazepines have the potential for abuse and should be used onlyas prescribed. As with opioids, an overdose of these drugs can be fatal.

Stimulants increase heart rate, blood pressure and metabolism, sometimesproviding feelings of exhilaration and energy and increased mentalalertness. Amphetamines such as methylphenidate (sometimes marketedunder the tradename RITALIN®) and dextroamphetamine (sometimes marketedunder the tradenames ADDERALL® and DEXEDRINE®) are often prescribed forthe treatment of narcolepsy, attention-deficit/hyperactivity disorder,and depression that has not responded to other treatments. They also maybe used for short-term treatment of obesity. Individuals may becomeaddicted to the sense of well-being and enhanced energy that stimulantscan generate. Taking high doses of stimulants repeatedly over a shorttime, however, can lead to feelings of hostility or paranoia.Additionally, taking high doses of stimulants may result in dangerouslyhigh body temperatures and an irregular heartbeat.

Preferred embodiments of the invention include a drug and amounts asfollows: oxycodone or a pharmaceutically acceptable salt thereof, whichis present in an amount of about 5 mg to about 400 mg; morphine or apharmaceutically acceptable salt thereof, which is present in an amountof about 15 mg to about 800 mg; hydromorphone or a pharmaceuticallyacceptable salt thereof, which is present in an amount of about 1 mg toabout 64 mg; hydrocodone or a pharmaceutically acceptable salt thereof,which is present in an amount of about 5 mg to about 400 mg; andoxymorphone or a pharmaceutically acceptable salt thereof, which ispresent in an amount of about 4 mg to about 80 mg.

In addition to one or more drugs, the diffusion layer contains one ormore polymers. Examples of polymers which can be used in the diffusionlayer include, but are not limited to, ethyl cellulose, a quaternaryammonium acrylic or methacrylic polymers, an acrylic or a methacrylicester copolymers or a mixture thereof, which can also be used assustained release agents. Common tradenames include various grades ofEUDRAGIT®s (all from Röhm), and SURELEASE® (from COLORCON®). Thepreferred polymers of the diffusion layer are acrylic or methacrylicpolymers and particularly ethyl acrylate or methyl methylacrylatedispersions. The use of diffusion polymers, preferably graduallyabrading polymers, is generally known in the pharmaceutical arts, and aswould be understood to one skilled in the art, any suitable graduallyabrading polymers or agent may be used in conjunction with the presentinvention and embodiments thereof.

Suitable waxes may replace a portion or all of the polymer in thediffusion layer. Suitable waxes include both synthetic and naturalwaxes, as well as wax-like substances, fats and fatty substances,hydrocarbons like paraffin, beeswax, carnauba wax, and the like,including combinations of these substances. These substances dissolvevery slowly or not at all in the GI tract. The use of wax-likesubstances is generally known in the pharmaceutical arts, and as wouldbe understood to one skilled in the art, any suitable wax-likesubstances may be used in conjunction with the present invention andembodiments thereof.

The diffusion layer may optionally also contain sustained or extendedrelease and/or enteric coating. Examples of such materials are celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid:acrylic ester copolymer,hydroxypropyl methylcellulose acetate succinate, shellac, celluloseacetate trimellitate, and mixtures thereof. The diffusion layer may alsocontain water-soluble polymers such as polyvinylpyrrolidone,hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethyleneglycol having a molecular weight of from 1,700 to 20,000 and polyvinylalcohol and monomers therefor and mixtures thereof. The use ofsustained, extended and enteric coating materials is generally known inthe pharmaceutical arts, and as would be understood to one skilled inthe art, any suitable sustained, extended and enteric coating materialsor similar agents may be used in conjunction with the present inventionand embodiments thereof.

In the preferred embodiments, for the barrier as well as the diffusionlayer, the acrylic coating is an acrylic lacquer used in the form of anaqueous dispersion that is commercially available from Röhm Pharma underthe tradename EUDRAGIT®.

The substantially homogeneous distribution of drug within the polymer ofthe diffusion layer allows for the release of drug at a defined desiredrate within the GI tract, for example, such that it slowly releases thedrug. The diffusion layer may be an immediate release layer or anextended release layer. The diffusion layer preferably maintains thesame release profile, preferably up to 24 hours, as conventional intactformulations, even when the layer is broken up into smaller pieces. Thepresence of the drug in the diffusion layer is thought to contribute tothe formation of pores in the polymers of the diffusion layer. Thepresence of pores allows for the gradual erosion of the diffusion layerand release of the drug. The release rate of drug can be adjusted bychanging the polymer pore size. For example, reduction in polymer poresize can reduce the release rate of the drug. Stretching or exposing thediffusion layer to solvents will also reduce polymer pore size andreduce the release rate of the drug.

The diffusion and barrier layers are bonded to each other. The layersmay be bonded by any method known in the art. In some embodiments, thelayers are chemically bonded, or preferably, they are physically bonded.In preferred embodiments, a physical bond is formed between layers byheat curing. In another preferred embodiment, the layers are in powderform and are physically bonded by using a tablet press. In someembodiments, the expansion and barrier layers may be manufactured asbulk tablets and stored for a period of time, preferably up to sevendays, as long as the barrier layer is not cured.

Preferably, the composition is configured such that when thepharmaceutical composition is physically compromised and particles ofthe pharmaceutical composition containing the diffusion layer and thebarrier layer are formed, the bond between the diffusion layer andbarrier layer within the particles is substantially preserved. In thepreferred embodiments of this invention, compromising the drug productin this manner will result in pieces of the diffusion layer and piecesof the barrier layer tightly bonded together within the particlesresulting from the compromising activity. Thus, in the preferredembodiments of this invention, the relative surface area of thediffusion layer will increase only marginally (e.g., no more than 50%,preferably no more than 25%, most preferably no more than 10%), whenparticles are produced in a range of 500 mesh to 8 mesh. The control ofdrug diffusion surface area in the preferred embodiments of thisinvention prevents a rapid release of the drug product from the drugproduct components, even if compromised.

The formation of a bond between the diffusion layer and the barrierlayer is important in achieving abuse resistance because when the dosageforms of the invention are physically compromised, the barrier layerprotects the inner side of the diffusion layer, preventing significantincrease in drug release. Therefore, the drug substance maintainsrelease gradually at substantially its designed rate from the outer sideof the diffusion layer.

The layer bonding design feature may be optimized by applying thediffusion layer immediately after the barrier layer is applied and thencuring them together.

The diffusion layer polymer is able to hold the drug within and thusprevent the dumping of drug substance after alteration of the dosageform. The barrier layer and optional expansion layer enhance the abuseresistant feature of the pharmaceutical composition.

Other components may be added to any or all of the various layersprovided that they do not interfere with the drug and provide a desiredbenefit to the pharmaceutical. Exemplary of such other components are:plasticizers, anti-adhesive, inert fillers, lipophilic agents andpigments used in a known manner. Tackiness of the water-dispersible filmforming substance may be overcome by simply incorporating ananti-adhesive in the coating. Examples of anti-adhesive are metallicstearates, microcrystalline cellulose, calcium phosphate, AEROSIL® 200,and talc. Those of ordinary skill in the art would understand the needfor and applicability of such other components to overcomemanufacturing, shelf-life or release profile issues.

Examples of plasticizers for use in accordance with the presentinvention include triacetin, acetylated monoglyceride, olive oil, acetyltributyl citrate, acetyl triethyl citrate, glycerin, sorbitol,polyethylene glycol, and polypropyleneglycol.

Fillers/diluents/binders may be incorporated such as sucrose, sorbitol,mannitol, various grades of lactose, various grades of microcrystallinecellulose, dextrins, maltodextrins, starches or modified starches,sodium phosphate, calcium phosphate, calcium carbonate, gelatin,polyvinylpyrrolidone, and sodium carboxymethylcellulose.

Disintegrants may be used such as cellulose derivatives, includingmicrocrystalline cellulose, low-substituted hydroxypropyl cellulose,croscarmellose sodium, alginic acid, insoluble polyvinlypyrrolidone, andsodium carboxymethyl starch.

Glidants and lubricants may be incorporated such as stearic acid,metallic stearates, talc, waxes, and glycerides with high meltingtemperatures, colloidal silica, sodium stearyl fumarate,polyethyleneglycols, and alkyl sulphates.

Surfactants may be employed such as non-ionic (various grades ofpolysorbate); anionic such as docusate sodium and sodium lauryl sulfate,and cationic such as benzalkonium chloride. An example of an amphotericsurfactant is 1,2-diacyl-L-phosphatidylcholine. The preferredsurfactants are TWEEN® 80, BRIJ®, and Nanoxyl-100.

Other appropriate pharmaceutically acceptable excipients may includecolorants, flavoring agents, pH adjusting agents, solubilizing agents,wetting agents, solvent resistant agents and buffering agents.

One or more other layers may be disposed under the expansion layer, orbetween the expansion layer and the barrier layer or above or on top ofthe diffusion layer. For example, in some embodiments, the expansionlayer is not in direct contact with the barrier layer, as one or morelayers may be disposed between the expansion layer and the barrierlayer. In other embodiments, the expansion layer can cover another layerthat is disposed under the expansion layer. In some embodiments, one ormore additional release layers comprising one or more additional drugscan be on top of the diffusion layer. In some embodiments, theadditional release layer can be an extended release layer or animmediate release layer. In some embodiments, both an extended releaselayer and an immediate release layer can be on top of the diffusionlayer. The one or more additional drugs can be any drug, including drugsthat may be part of the diffusion layer of the composition, such ascentral nervous system stimulants and depressants such as opioids,barbiturates, benzodiazepines, and amphetamines. Preferably, the layeron top of the diffusion layer is an immediate release layer, and drugsin the immediate release layer include, but are not limited toacetaminophen and nonsteroidal anti-inflammatory drugs.

Because of the described features above, the abuse potential of thepharmaceutical composition of the present invention is decreased.Further, the features can in some embodiments deter a patient fromcutting a dosage form into smaller pieces containing a fraction of thedosage of the intact tablet. For example, a patient seeking to cut an 80mg tablet into four 20 mg tablet pieces would be unable to achieve thenecessary therapeutic effect with the cut 20 mg tablet pieces, incomparison to uncompromised 20 mg tablets. This is the case, because inthis embodiment of the invention, the cut 20 mg tablet pieces would notrelease the full 20 mg amount of drug in the tablet piece.

Preferably, when administered properly in an intact form, the drug isreleased at a desired release rate from the diffusion layer, and theremainder of the pharmaceutical composition passes through the patient'sbody in an inert manner, because the barrier layer prevents theremainder of the composition from being broken down in the GI tract. Thedesired release rate may be the release rate typically obtained from theintended use, such as described in the prescribing informationassociated with a commercial drug product.

In a preferred embodiment of the invention wherein the compositioncomprises an expansion layer, physically compromising the drug productresults in the expansion layer being dispersed between particlescontaining diffusion layer and barrier layer components, as a componentof the particles containing diffusion layer and barrier layercomponents, or both. Thus, in preferred embodiments of the invention,once exposed to bodily fluids or other liquids, the particles containingthe diffusion layer and barrier layer components become embedded in theswelled expansion layer, such that the net diffusion of the drugsubstance into such bodily fluids or other liquids occurs atsubstantially lower rates than those observed from the diffusion out ofthe uncompromised drug product.

In preferred embodiments of the invention, the resulting pharmaceuticalcomposition will have both a mechanism to control and largely maintainthe rate of diffusion of the drug substance from the drug substancecontaining compartments of the composition, as well as a mechanism toretard diffusion of the drug substance from the drug-substancecontaining compartments of the composition and to retain a substantialproportion of the drug substance once the composition is compromised andexposed, in whole or in part, to a liquid. A benefit of the invention isthat it will be difficult for any person intending to abuse the drugsubstance by rapidly extracting the drug substance from the drug productthrough some kind of compromising activity and snorting, swallowing orinjecting. As a result, improper administration of the presentinvention, compared to conventional formulations, results in a decreasedintensity and quality of euphoria, as well as a decrease in the rate atwhich the euphoria occurs. Therefore, abusers hoping to attain a “high”or experience euphoria by improperly using the present composition maybe unable to achieve the desired “high” or euphoria. Rather, a lessintense effect, if any, is achieved at a much slower rate. Unlesssophisticated and time-consuming extraction methods are employed, byapplying the invention, a substantial share of the drug substance willbecome trapped in and not be separable from the resulting compromiseddrug product, thus reducing the overall bioavailability upon snorting,swallowing or injecting.

In preferred embodiments, the present composition, when compromised,releases substantially the same or a lower percentage of drug comparedto an intact, uncompromised composition. In preferred embodiments,within a time period selected from the group consisting of 2 hours, 4hours, 8 hours and 16 hours, a compromised composition release no morethan 90%, more preferably no more than 75%, and more preferably no morethan 60% of the drug compared to intact, uncompromised tablets over thesame amount of time.

The mechanisms and benefits described above are measurable byconventional pharmaceutical in vivo and in vitro analytical techniques,such as in vivo plasma measurements or in vitro drug dissolution. Withthese techniques, the release of drug substance present in thepharmaceutical composition over time can be monitored and expressed as areleased percentage of the drug substance originally present suchcomposition. In preferred embodiments of the invention, the percentageof the drug substance released will be substantially lower when apharmaceutical composition employing the invention is physicallycompromised and then tested in an in vitro dissolution test.

In discussing release characteristics of products of the invention, thedosage form comprising an effective amount of a drug has a dissolutionrate in vitro that is measured by the USP Paddle Method of U.S.Pharmacopoeia, with USP Apparatus I, at 100 rpm (basket) at 900 mLaqueous buffer at pH 1.6 and 7.2 and at 37° C.

Preferably, the in vitro release is about 5% to about 50% (by wt.) drugsubstance released after 1 hour, from about 20% to about 65% (by wt.)drug substance released after 4 hours, from about 35% to about 85% (bywt.) drug substance released after 8 hours and greater than 60% (by wt.)drug substance released after 16 hours; more preferably about 5% toabout 40% after 1 hour, about 15% to about 60% after 4 hours; about 40%to about 80% after 8 hours; and about 50% to about 90% after 16 hours;more preferably about 10% to about 35% after 1 hour, about 15% to about55% after 4 hours; about 35% to about 75% after 8 hours; and about 50%to about 80% after 16 hours; most preferably about 10% to about 30%after 1 hour, about 25% to about 60% after 4 hours; about 40% to about80% after 8 hours; and about 55% to about 75% after 16 hours. Themechanisms and benefits described above are also measurable byconventional pharmacokinetic research techniques typically employed inthe characterization of drug kinetics in human patients or othermammals.

The most relevant pharmacokinetic parameters for understanding thefeatures and benefits of the invention are Cmax (maximum blood serumconcentration of the drug substance and/or active metabolites) and AUC(area under the serum concentration curve: the integral of the bloodserum concentration of the drug substance and/or active metabolites overtime). In preferred embodiments of the invention, when thepharmaceutical composition is administered in physically compromisedform to a subject, the Cmax and/or AUC achieved after a time periodselected from the group consisting of 2 hours, 4, hours, 8 hours, 12hours, 24 hours, and 48 hours after administration is substantially thesame or lower, preferably about 20-75% lower, than the Cmax and/or AUCachieved when the pharmaceutical composition is administered in anintact form.

One embodiment of the invention relates to a pharmaceutical compositionconfigured such that when the pharmaceutical composition is administeredin physically compromised form to a subject, the Cmax and/or AUCresulting from the compromised drug product achieved after a time periodselected from the group consisting of 2 hours, 4, hours, 8 hours, 12hours, 24 hours, and 48 hours after administration, will be lower,preferably about 20-75% lower, than the Cmax and/or AUC resulting froman equal amount of a physically compromised bioequivalent compositionthat does not employ means for deterring abuse. A “bioequivalent” drugcomposition refers to an intact composition which contains the same drugand has an AUC and Cmax within the range of 80 to 125% of the AUC andCmax of the reference drug composition.

Another embodiment of the invention relates to a pharmaceuticalcomposition configured such that when the pharmaceutical composition isadministered in physically compromised form to a subject, the Cmax/AUCratio resulting from the compromised drug product achieved after a timeperiod selected from the group consisting of 2 hours, 4, hours, 8 hours,12 hours, 24 hours, and 48 hours after administration, will be or lower,preferably 20-75% lower, than the Cmax/AUC ratio resulting from aphysically compromised bioequivalent drug product that does not comprisemeans for deterring abuse.

Another preferred embodiment of the invention is an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least50%, preferably at least 60%, of the amount of drug is released after 8hours and when the pharmaceutical composition is administered inphysically compromised form no more than 40%, preferably no more than35%, more preferably no more than 30%, and most preferably no more than25%, of the amount of drug is released after 1 hour. Preferably, whenthe pharmaceutical composition is administered in physically compromisedform no more than 35%, more preferably no more than 30%, and mostpreferably no more than 25%, of the amount of drug is released in 15minutes.

Another preferred embodiment of the invention is an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least90% of the amount of drug is released after 1 hour and when thepharmaceutical composition is administered in physically compromisedform no more than 75%, preferably no more than 60%, of the amount ofdrug is released after 1 hour.

The present invention also relates to an oral pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the intensity of the euphoria is substantially thesame or lower than the intensity of the euphoria achieved afteradministration of a physically compromised bioequivalent composition notcomprising means for deterring abuse. Euphoria is a high or feeling ofextreme elation, which is often experienced after an abuser isadministered a pharmaceutical composition containing a central nervoussystem drug. The amount or intensity of euphoria can be measured in anumber of different ways. Methods or techniques of measuring euphoriaare sometimes similar to methods or techniques of measuring otherconditions, such as pain. For example, the amount or intensity ofeuphoria can be measured in a numerical or linear scale, and the personexperiencing the euphoria can quantify or rate the amount or intensityof the euphoria. For example, in some embodiments, the amount orintensity of euphoria can be measured on a scale from 0 to 10, wherein ahigh amount of euphoria is designated by the number 10, and no euphoriais designated by the number 0. Similarly, in some embodiments, theamount or intensity of euphoria can be measured on a linear scale,wherein one end of the line represents no euphoria, and the opposite endof the line represents a high amount of euphoria. In some embodiments,the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the intensity of the euphoria is substantially thesame or preferably less than 10%, more preferably less then 30%, andmore preferably less than 50% than the intensity of the euphoriaachieved after administration of a physically compromised bioequivalentcomposition not comprising means for deterring abuse.

The drug composition of the present invention is preferably independentof pH in its release profile. Further, there is preferably nosignificant change (preferably, less than 10% change) in the releaserate of the formulation after 3 months of storage at 40° C. at 75%relative humidity, when measured by the USP basket method of U.S.Pharmacopoeia, with USP Apparatus I, at 100 rpm (basket) at 900 mLaqueous buffer at pH 1.6 and 7.2 and at 37° C.

All references cited herein are hereby incorporated by reference intheir entirety.

The following examples are employed to demonstrate and illustrate thepresent invention.

Example 1 Mannitol—90 mg Microcrystalline Cellulose—50 mg CARBOPOL®71G—128 mg

Hydroxypropyl Methylcellulose, type 2910—128 mg

(METHOCEL™ K4M CR) Magnesium Stearate—4 mg

Procedure: Mannitol, Microcrystalline Cellulose, CARBOPOL® 71 G, andMETHOCEL™ K4M CR were sifted through # 20 mesh and blended in a blenderfor 10 minutes. Magnesium Stearate was sifted through #40 mesh and addedin to the blender and mixed for 5 minutes to lubricate the blend. Thefinal blend was compressed at 400-mg tablet weight and hardness between8-15 kp.

Example 2 Mannitol—22.5 mg Microcrystalline Cellulose—12.5 mg CARBOPOL®71G—32 mg

Hydroxypropyl Methylcellulose, type 2910—32 mg

(Methocel™ K4M CR) Magnesium Stearate—1 mg

Procedure: Mannitol, Microcrystalline Cellulose, CARBOPOL® 71 G, andMETHOCEL™ K4M CR were sifted through # 20 mesh and blended in a blenderfor 10 minutes. Magnesium Stearate was sifted through #40 mesh and addedin to the blender and mixed for 5 minutes to lubricate the blend. Thefinal blend was compressed at 100-mg tablet weight and hardness between4-9 kp.

Example 3 Mannitol—135 mg Microcrystalline Cellulose—75 mg CARBOPOL®71G—192 mg

Hydroxypropyl Methylcellulose, type 2910—192 mg (METHOCEL™ K4M CR)

Magnesium Stearate—6 mg

Procedure: Mannitol, Microcrystalline Cellulose, CARBOPOL® 71 G, andMETHOCEL™ K4M CR were sifted through # 20 mesh and blended in a blenderfor 10 minutes. Magnesium Stearate was sifted through #40 mesh and addedin to the blender and mixed for 5 minutes to lubricate the blend. Thefinal blend was compressed at 600-mg tablet weight and hardness between8-15 kp.

Example 4 Mannitol—70 mg Microcrystalline Cellulose—50 mg CARBOPOL™71G—128 mg

Hydroxypropyl Methylcellulose, type 2910—128 mg (METHOCEL™ K4M CR)Croscarmellose sodium—20 mg (AC-DI-SOL®)

Magnesium Stearate—4 mg

Procedure Mannitol, CARBOPOL® 71 G, Microcrystalline Cellulose,METHOCEL™ K4CR, and AC-DI-SOL® were sifted through # 20 mesh and blendedin a blender for 10 minutes. Magnesium Stearate was sifted through #40mesh and added in to the blender and mixed for 5 minutes to lubricatethe blend. The final blend was compressed at 400-mg tablet weight andhardness between 8-15 kp.

The combination of CARBOPOL® and METHOCEL™ (Example 4) is a preferredformulation as it provided relatively rapid expansion capability. Theaddition of super disintegrant like AC-DI-SOL® aids in expandingcapability. Also different expansion layer tablet weight as shown inexample 1 through 3 produced the same desired characteristics of theexpansion layer.

Example 5 Mannitol—45 mg Microcrystalline Cellulose—25 mg CARBOPOL™71G—64 mg

Hydroxypropyl Methylcellulose, type 2910—64 mg (METHOCEL™ K4M CR)

Magnesium Stearate—2 mg

Procedure: Mannitol, CARBOPOL® 71 G, Microcrystalline Cellulose, andMETHOCEL™ K4CR were sifted through # 20 mesh and blended in a blenderfor 10 minutes. Magnesium Stearate was sifted through #40 mesh and addedin to the blender and mixed for 5 minutes to lubricate the blend. Thefinal blend was compressed at 400-mg tablet weight and hardness between8-15 kp.

Example 6

Expansion layer tablet (example 4)—370 g

EUDRAGIT®NE 30D Dispersion—300 g

Calcium Stearate powder—15 gSimethicone solids—0.15 gPurified water—85 g

Procedure: Expansion layer tablet having 400 mg unit weight were loadedin to a conventional coating pan and EUDRAGIT® NE30D, SimethiconeEmulsion 30%, Calcium Stearate & Purified Water suspension was sprayedon to the expansion layer tablet using conventional coating techniquescreating the barrier layer. The suspension was prepared by first addingSimethicone Emulsion into the Purified Water while mixing. After about10 minutes of mixing, Calcium Stearate powder was added while mixing.After about 15 minutes of mixing, the Calcium Stearate suspension washomogenized for 10 minutes at a medium speed using a suitablehomogenizer. In a separate container, required amount of Eudragit® NE 30D was added and while mixing, Calcium Stearate suspension was added. Thefinal coating suspension was mixed for about 20 minutes before sprayingonto the tablets. The coated barrier layer tablets were then cured at60° C. for 1-3 hours to stabilize the film. The cured tablets were thenused for the diffusion layer. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 2-10 g/m in.

Example 7

Expansion layer tablet (example 4)—370 g

EUDRAGIT® NE 30D Dispersion—300 g Calcium Stearate—15 g

Simethicone Emulsion solids—0.15 gPurified water—85 g

Procedure: The preparation of the coating suspension and the coatingprocess of the barrier layer were same as the previous example. In thisexample the diffusion layer coat was immediately applied after barrierlayer coat was over and then the tablets were cured at 60° C. for 1-3hours. Throughout the coating process, product temperature of 30-35° C.was maintained. The spray rate range was between 2-10 g/min.

Example 8

Expansion layer tablet (example 5)—400 g

EUDRAGIT® NE 30D Dispersion—150 g Calcium Stearate—5 g

Simethicone Emulsion solids—0.05 gPurified water—28 g

Procedure: Expansion layer tablet having 200 mg unit weight were loadedin to a conventional coating pan. The coating suspension containingEUDRAGIT® NE30D, Calcium Stearate, Simethicone Emulsion 30% suspensionand Purified Water was prepared similar to the example 6 and was sprayedon to the expansion layer tablet using conventional coating techniques,creating the barrier layer. The application of the barrier layer,diffusion layer and curing process was similar to Example 7. Throughoutthe coating process, product temperature of 30-35° C. was maintained.The spray rate range was between 2-10 g/min.

Example 9

Expansion layer tablet (example 3)—600 g

EUDRAGIT® NE 30D Dispersion—150 g Aerosil 200—5 g

Procedure: Expansion layer tablet having 600 mg unit weight were loadedin to a conventional coating pan and EUDRAGIT® NE30D, Aerosil 200 &Purified Water suspension was sprayed on to the expansion layer tabletusing conventional coating techniques, creating the barrier layer. Thecoating suspension was prepared by adding Aerosil 200 into the requiredquantity of Eudragit® NE30D while mixing. The final coating suspensionwas mixed for about 20 minutes before spraying onto the tablets. Theapplication of the barrier layer, diffusion layer and curing process wassimilar to Example 7 & 8. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 2-10 g/min.

Example 10

Expansion layer tablet (example 2)—400 g

EUDRAGIT® NE 30D Dispersion—150 g Talc—15 g

Purified water—50 g

Procedure: Expansion layer tablet having 100 mg unit weight were loadedin to a conventional coating pan and EUDRAGIT® NE30D, Talc & PurifiedWater dispersion was sprayed on to the expansion layer tablet usingconventional coating techniques, creating the barrier layer. The Barrierlayer coating suspension was prepared by mixing Talc with the requiredamount of the purified water while mixing. After about 15 minutes ofmixing, the suspension was homogenized for 10 minutes at a medium speed.In a separate container, Eudragit NE30D was added. While mixing, Talcsuspension was added and the resulting coating suspension was mixed forabout 20 minutes for spraying onto the tablets. The application of thebarrier layer, diffusion layer and curing process was similar to Example7, 8, and 9. The barrier layer separates the diffusion layer andexpansion layer and also makes the tablet resistant to crushing,smashing and other physical means of applying pressure.

Example 11

Expansion layer tablet (example 4)—370 g

EUDRAGIT® NE 30D Dispersion—200 g EUDRAGIT® RS 30D Dispersion—100 gTalc—25 g

Purified water—142 gProcedure: Expansion layer tablet having 400 mg unit weight were loadedin to a conventional coating pan and EUDRAGIT® NE30D, EUDRAGIT® RS30D,Talc & Purified Water suspension was sprayed on to the expansion layertablet using conventional coating techniques, creating the barrierlayer. The coating suspension preparation was very similar to theprevious example. It is possible to enhance the water impermeablecharacteristic of EUDRAGIT® NE30D polymer by incorporating EUDRAGIT®RS30D polymer in the barrier layer coating.

The barrier coated tablet strength and water impermeabilitycharacteristic was independent of anti-tacking agent such as Talc,Aerosil 200, Calcium Stearate, Magnesium Stearate and GlycerylMonostearate. The barrier coat of 5-95 weight % of dry matter calculatedbased on the starting weight of the expansion layer tablet providedrelatively crush resistant and water impermeable tablet. The preferredrange for the barrier coat was between 10-60 weight %. The barrier coatand subsequent diffusion polymer coat were inseparable upon smashing,grinding or crushing if diffusion layer was applied immediately afterthe barrier coat and then cured together.

Example 12

Barrier coated tablets (example 7)—475 g

Oxycodone Hydrochloride—37 g

EUDRAGIT®NE 30D dispersion—175 g

Tween® 80—1.5 g Aerosil® 200—2.0 g Purified Water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The drug-polymercoat consisting of Oxycodone Hydrochloride, Tween® 80, Aerosil® 200 andEUDRAGIT® NE30D suspension was sprayed on to the barrier coated tablet.The suspension was prepared by first adding Tween® 80 in the requiredamount of the Purified Water while mixing. The mixing was continued forabout 10 more minutes. While mixing, Aerosil® 200 powder was added intothe previous step suspension and mixed for about 10 minutes. In aseparate container, required amount of Eudragit NE 30 D was added andwhile mixing, Oxycodone hydrochloride powder was added and mixing wascontinued for about 15 more minutes to achieve the homogenoussuspension. While mixing, suspension-containing Tween-Aerosil was addedand the final suspension was mixed for about 20 minutes before sprayingonto the tablets. The diffusion layer coated tablets were then cured at60° C. for 1-3 hours to stabilize the film. Throughout the coatingprocess, product temperature of 30-35° C. was maintained. The spray raterange was between 5-15 g/min.

Example 13

Barrier coated tablets (example 7)—475 g

Oxycodone Hydrochloride—37 g

EUDRAGIT® NE 30D dispersion—275 g

Calcium Stearate—6 g

Simethicone Emulsion solids—0.06 gPurified water—34.4 g

Procedure: After completion of the barrier coating, the diffusion layercoat was immediately applied in a conventional coating pan. Thesuspension was prepared by first adding Simethicone Emulsion into thePurified Water while mixing. After about 10 minutes of mixing, CalciumStearate powder was added while mixing. After about 15 minutes ofmixing, the Calcium Stearate suspension was homogenized for 10 minutesat a medium speed using a suitable homogenizer. In a separate container,required amount of Eudragit NE 30 D was added and while mixing,Oxycodone hydrochloride powder was added and continued mixing for about15 minutes to achieve the homogenous suspension. In this homogenoussuspension, Calcium Stearate suspension was added. The final coatingsuspension was mixed for about 20 minutes before spraying onto thetablets. The diffusion-layered tablets were then cured at 60° C. for 1-3hours to stabilize the film. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 14

Barrier coated tablets (example 11)—485 g

Oxycodone Hydrochloride—74 g

EUDRAGIT® NE 30D dispersion—350 g

Tween 80—2 g Calcium Stearate—11 g

Simethicone Emulsion solids—0.11 gPurified water—60 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Oxycodone hydrochloride, EUDRAGIT® NE30D, CalciumStearate, Simethicone Emulsion dispersion 30% and Purified Watersuspension was sprayed on to the barrier coated tablet. The suspensionwas prepared by first adding Simethicone Emulsion into the PurifiedWater while mixing. After about 10 minutes of mixing, Calcium Stearatepowder was added while mixing. After about 15 minutes of mixing, theCalcium Stearate suspension was homogenized for 10 minutes at a mediumspeed using a suitable homogenizer. In a separate container, requiredamount of Eudragit NE 30 D was added and while mixing, Tween® 80 wasadded and mixing was continued for about 10 minutes. After that,Oxycodone hydrochloride powder was added and while mixing. After about15 minutes of mixing Calcium Stearate suspension was added. The finalcoating suspension was mixed for about 20 minutes before spraying ontothe tablets. The diffusion-layered tablets were then cured at 60° C. for1-3 hours to stabilize the film. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 15

Barrier coated tablets (example 8)—450 g

Oxycodone Hydrochloride—10 g

EUDRAGIT® NE 30D dispersion—100 g

Aerosil 200—2 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Oxycodone hydrochloride, EUDRAGIT® NE30D, Aerosil®200 & Purified Water dispersion was sprayed on to the barrier coatedtablet and then the diffusion layer coated tablets were then cured at60° C. for 1-3 hours to stabilize the film. Refer to example 12 for thecoating suspension preparation.

Example 16

Barrier coated tablets (example 7)—475 g

Hydrocodone Bitartrate—9.25 g

EUDRAGIT® NE 30D dispersion—155 gAEROSIL® 200 powder—5 g

TWEEN 80®—1.5 g

Purified water—185 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer dispersion was prepared by first adding TWEEN® 80 and AEROSIL® 200powder into Purified water and mixing the suspension for about 10minutes. Then Hydrocodone Bitartrate powder was added into thesuspension. The suspension was mixed for about 15 minutes to achieve theuniform distribution of the drug. In a separate container add therequired amount of Eudragit NE 30D. While mixing, add theactive-Tween-Aerosil suspension in the Eudragit NE30D dispersion and mixfor not less than 20 minutes before spraying on to the barrier coatedtablet. The diffusion layer coated tablets were then cured at 60° C. for1-3 hours to stabilize the film. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 17

Barrier coated tablets (example 7)—475 g

Morphine Sulfate—55.6 g

EUDRAGIT® NE 30D dispersion—275 g

Aerosil 200—5.0 g

Purified water—150 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Morphine Sulfate, EUDRAGIT® NE30D, Aerosil 200 &Purified Water dispersion was sprayed on to the barrier coated tabletand then the diffusion layer coated tablets were then cured at 60° C.for 1-3 hours to stabilize the film. The diffusion layer dispersion wasprepared by first adding AEROSIL® 200 powder into Purified water andmixing the suspension for about 10 minutes. Then add the Morphinesulfate powder into the suspension. Mix until uniform suspension isachieved. The suspension was homogenized for about 10 minutes at amedium speed. In a separate container add the required amount ofEudragit NE 30D. While mixing, add the drug-Aerosil suspension in theEudragit NE30D dispersion and mix for not less than 20 minutes beforespraying on to the barrier coated tablet.

Example 18

Barrier coated tablets (example 7)—475 g

Hydromorphone Hydrochloride—14.8 g

EUDRAGIT® NE 30D dispersion—250 g

Aerosil® 200—5.0 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Hydromorphone Hydrochloride, EUDRAGIT® NE30D,Aerosil® 200 & Purified Water dispersion was sprayed on to the barriercoated tablet and then the diffusion layer coated tablets were thencured at 60° C. for 1-3 hours to stabilize the film. Throughout thecoating process, product temperature of 30-35° C. was maintained. Thespray rate range was between 5-15 g/min. Refer to the previous examplefor the preparation of the suspension.

Example 19

Barrier coated tablets (example 7)—475 g

Oxymorphone Hydrochloride—37 g

EUDRAGIT® NE 30D dispersion—220 g

Tween® 80—2.5 g Aerosil® 200—5.0 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Oxymorphone Hydrochloride, EUDRAGIT® NE30D, Tween®80, Aerosil® & Purified Water dispersion was sprayed on to the barriercoated tablet. The diffusion layer dispersion was prepared by firstadding TWEEN® 80 and AEROSIL® 200 powder into Purified water and mixingthe suspension for about 10 minutes. Then Oxymorphone hydrochloridepowder was added into the suspension. The suspension was mixed for about15 minutes to achieve the uniform distribution of the drug. In aseparate container add the required amount of Eudragit NE 30D. Whilemixing, add the active-Tween-Aerosil suspension in the Eudragit NE30Ddispersion and mix for not less than 20 minutes before spraying on tothe barrier coated tablet. The diffusion layer coated tablets were thencured at 60° C. for 1-3 hours to stabilize the film. Throughout thecoating process, product temperature of 30-35° C. was maintained. Thespray rate range was between 5-15 g/min.

Example 20

Barrier coated tablets (example 8)—475 g

Dexmethylphenidate Hydrochloride—10 g

EUDRAGIT® NE 30D dispersion—100 g

Aerosil 200—1 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Dexmethylphenidate Hydrochloride, EUDRAGIT® NE30D,Aerosil® 200 & Purified Water dispersion was sprayed on to the barriercoated tablet and then the diffusion layer coated tablets were thencured at 60° C. for 1-3 hours to stabilize the film. Throughout thecoating process, product temperature of 30-35° C. was maintained. Thespray rate range was between 5-15 g/min.

Example 21

Barrier coated tablets (example 10)—450 g

Zaleplon—20 g

EUDRAGIT® NE 30D dispersion—100 g

Aerosil® 200—1 g Tween® 80—5 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Zaleplon, EUDRAGIT® NE30D, Aerosil® 200, Tween® 80,& Purified Water dispersion was sprayed on to the barrier coated tablet.The diffusion layer dispersion was prepared by first adding TWEEN® 80and AEROSIL® 200 powder into Purified water and mixing the suspensionfor about 10 minutes. Then Zaleplon powder was added into thesuspension. The suspension was mixed for about 15 minutes andhomogenized for 10 minutes to achieve the uniform distribution of thedrug. In a separate container add the required amount of Eudragit NE30D. While mixing, add the active-Tween-Aerosil suspension in theEudragit NE30D dispersion and mix for not less than 20 minutes beforespraying on to the barrier coated tablet. The diffusion layer coatedtablets were then cured at 60° C. for 1-3 hours to stabilize the film.Throughout the coating process, product temperature of 30-35° C. wasmaintained. The spray rate range was between 5-15 g/min.

Example 22

Barrier coated tablets (example 9)—695 g

Propranolol Hydrochloride—80 g

EUDRAGIT® NE 30D dispersion—150 g

Aerosil® 200—5 g TWEEN® Solution—1 g

Purified water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Propranolol hydrochloride, Aerosil® 200, TWEEN® 80,EUDRAGIT® NE30D, and Purified Water dispersion was sprayed on to thebarrier coated tablet and then the diffusion layer coated tablets werethen cured at 60° C. for 1-3 hours to stabilize the film. Throughout thecoating process, product temperature of 30-35° C. was maintained. Thespray rate range was between 5-15 g/min.

Example 23

Barrier coated tablets (example 6)—475 g

Tramadol Hydrochloride—92.6 g

EUDRAGIT® NE 30D dispersion—290 g

Tween® 80—0.5 g AEROSIL® 200—5 g

Purified water—250 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The diffusionlayer consisting of Tramadol hydrochloride, EUDRAGIT® NE30D, Tween® 80,AEROSIL® 200 and Purified Water dispersion was sprayed on to the barriercoated tablet and then the diffusion layer coated tablets were thencured at 60° C. for 1-3 hours to stabilize the film. Throughout thecoating process, product temperature of 30-35° C. was maintained. Thespray rate range was between 5-15 g/min.

Example 24 Multi-Drug Product, Conventional Immediate-Release

Barrier coated tablets (example 8)—450 g

Oxycodone Diffusion Coat:

Oxycodone Hydrochloride—10 g

EUDRAGIT® NE 30D dispersion—100 g

Aerosil® 200—1 g

Purified water—100 g

Sub Coat, Acetaminophenone Coat and Seal Coat:

5% HPMC solution Sub-coat—100 g

Acetaminophenone Powder—2000 g

10% HPMC solution—1000 g

Purified Water—1000 g

5% HPMC Seal coat—100 g

Procedure: After completion of the barrier coating, the Oxycodonehydrochloride diffusion layer was immediately applied in a conventionalcoating pan. The diffusion layer consisting of Oxycodone hydrochloride,EUDRAGIT® NE30D, Aerosil® 200 & Purified Water suspension was sprayed onto the barrier coated tablet. The diffusion layer coated tablets werethen cured at 60° C. for 1-3 hours to stabilize the film. Once thecuring process was completed, 5% HPMC sub-coat was applied followed byAcetaminophenone coat. The Acetaminophenone HPMC-suspension was sprayedon to the tablets at 5-25 g/min. The Acetaminophenone suspension wasprepared by first mixing 10% Methocel solution with the requiredquantity of the purified water and then suspending the active drug whilemixing. The suspension was mixed for about 15 minutes and thenhomogenized for 10 minutes before spraying on to the tablets.Alternatively, the active drug powder can be dusted into the coating pansuing a powder feeder and 10% HPMC solution can be sprayed using a spraynozzle. The product temperature was kept around 30-35° C. Once all ofthe suspension was applied, HPMC seal coat was applied. The tablets weredried for 5 minutes at product temperature between 38-40° C. beforedischarging from the coating pan.

Example 25

Barrier coated tablets—475 g

Diffusion Layer Coating: Oxycodone Hydrochloride—37 g

EUDRAGIT® NE 30D dispersion—275 g

Tween® 80—2.5 g Calcium Stearate—6 g

Simethicone solids—0.06 g

Purified Water—34.4 g Sustained-Release Layer Coating:

EUDRAGIT® NE 30D dispersion—30 g

HPMC 10% Solution—30 g Aerosil® 200—2.5 g Purified Water—66 g

After completion of the barrier coating, the diffusion layer wasimmediately applied in a conventional coating pan. The diffusion layerconsisting of Oxycodone hydrochloride, EUDRAGIT® NE30D, Tween® 80,Calcium Stearate, Simethicone Emulsion 30% dispersion and Purified Watersuspension was sprayed on to the barrier coated tablet followed by thesustained-release coating suspension. The sustained-release coatingsuspension was prepared by mixing (about 15 minutes) Eudragit® NE 30D,10% HPMC solution, Aerosil® 200 and Purified Water. After the completionof the coating, the coated tablets were then cured at 60° C. for 1-3hours to stabilize the film. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 26

Diffusion Layer tablets (example 13)—600 g

Opadry 85F18422 White Powder—50 g Purified Water—250 g

After completion of Diffusion coat, the color coat is immediatelyapplied in a conventional coating pan. The Color coating suspension isprepared by suspending Opadry powder in Purified water. About 300 g ofColor Suspension is sprayed onto the diffusion layer coated tablets at aspray rate of 5-15 g/min. The product temperature of 36-38° C. ismaintained throughout the process.

Example 27

Barrier coated tablets (example 8)—450 g

Oxycodone Hydrochloride—10 g Morphine Sulfate—20 g

EUDRAGIT®NE 30D dispersion—125 g

Tween® 80—1.0 g Aerosil® 200—2.0 g Purified Water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The drug-polymercoat consisting of Oxycodone Hydrochloride, Morphine Sulfate, Tween® 80,Aerosil® 200 and EUDRAGIT® NE30D suspension was sprayed on to thebarrier coated tablet. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 28

Barrier coated tablets (example 7)—475 g

Oxycodone Hydrochloride—9.3 g Morphine Sulfate—18.5 g

EUDRAGIT®NE 30D dispersion—275 g

Tween® 80—2.0 g Aerosil® 200—2.5 g Purified Water—100 g

Procedure: After completion of the barrier coating, the diffusion layerwas immediately applied in a conventional coating pan. The drug-polymercoat consisting of Oxycodone Hydrochloride, Morphine Sulfate, Tween® 80,Aerosil® 200 and EUDRAGIT® NE30D suspension was sprayed on to thebarrier coated tablet. Throughout the coating process, producttemperature of 30-35° C. was maintained. The spray rate range wasbetween 5-15 g/min.

Example 29 Abuse-Resistant Capsule Formulation

Expansion layer Mannitol 52.5 mg Microcrystalline Cellulose 37.5 mgCarbopol 71G   96 mg Hydroxypropyl Methylcellulose, type 2910   96 mg(METHOCEL ™ K4M CR) Croscarmellose sodium   15 mg (AC-DI-SOL ®)Magnesium Stearate   3 mg HPMC Size # 2 Capsules   60 mg

Barrier layer EUDRAGITNE ® NE 30D solids 97.3 mg Calcium Stearate 16.2mg Simethicone Emulsion  0.2 mg Purified water —

Diffusion layer Oxycodone Hydrochloride   40 mg EUDRAGIT ® NE 30D solids63.5 mg Aerosil ® 200  2.5 mg Tween 80 ® 80  1.5 mg Purified water —

Sustained-Release coat EUDRAGIT ® NE 30D solids  15 mg Aerosil ® 200 2.5mg HPMC E6 solids   5 mg Purified water —

Color coat Opadry 85F18422 Powder 30 mg Purified Water —

Procedure: Mannitol, Microcrystalline Cellulose, CARBOPOL® 71 G, andMETHOCEL™ K4M CR were sifted through # 20 mesh and blended in a blenderfor 10 minutes. Magnesium Stearate was sifted through #40 mesh and addedin to the blender and mixed for 5 minutes to lubricate the blend. Thefinal blend was encapsulated into HPMC Size # 2 Capsules at 300-mgweight. The Expansion layer Capsules were loaded in to a conventionalcoating pan and EUDRAGIT® NE30D, Calcium Stearate, Simethicone Emulsion& Purified Water suspension was sprayed on to the capsules creating thebarrier layer. After completion of the barrier coating, the diffusionlayer followed by the sustained-release coating was immediately appliedin a conventional coating pan. The Sustained-release coated capsuleswere then cured at 60° C. for 1-3 hours to stabilize the film. After thecuring process, color coat was applied. Throughout the coating process,product temperature of 30-35° C. was maintained. The spray rate rangewas between 5-15 g/min.

Example 30 Abuse-Resistant Pellet Formulation

Expansion layer Mannitol 35 mg Microcrystalline Cellulose 25 mg Carbopol71G 64 mg Hydroxypropyl Methylcellulose, type 2910 64 mg (METHOCEL ™ K4MCR) Croscarmellose sodium 10 mg (AC-DI-SOL ®) Methocel E6 solids 20 mgPurified Water —

Barrier layer EUDRAGIT ® NE 30D solids 97 mg EUDRAGIT ® RS 30D solids 32mg Talc Powder 50 mg Purified water —

Diffusion layer Oxycodone Hydrochloride 40 mg EUDRAGIT ® NE 30D solids89 mg Aerosil ® 200  2 mg Purified water —

Tablet Formula Avicel PH 102 100 mg Avicel PH 200 100 mg MagnesiumStearate  8 mg

Color coat Opadry 85F18422 Powder 30 mg Purified Water —

One or more active ingredients may be placed into one or more individualpellet. In some embodiments, two or more different types of pellets maybe used together, wherein each type of pellet contains a differentactive ingredient.

Procedure: Mannitol, Microcrystalline Cellulose, CARBOPOL® 71 G, andMETHOCEL™ K4M CR were sifted through # 20 mesh and loaded in a Fluid BedDryer/Coater fitted with a Top-Spray coating nozzle. A 10% Methocelsolution was sprayed as a binder solution to granulate the powder. Afterdesired granulation was achieved, the granules are dried to moisturelevel of about 2%. The Dried granules are discharged from the Fluid Bedmachine and sized using suitable milling machine such as StokesOscillating granulator. The dry-sized granules were then loaded into thesame Fluid bed dryer/coater and EUDRAGIT® NE30D, Eudragit® RS 30D, Talc& Purified Water dispersion was sprayed on to the pellets/granulescreating the barrier layer. After completion of the barrier coating, thediffusion layer was immediately applied. The diffusion layer consistingof Oxycodone hydrochloride, EUDRAGIT® NE30D, Aerosil® 200 and PurifiedWater suspension was sprayed on to the barrier coated capsules and thenthe diffusion layer coated pellets were cured at 60° C. for 1-3 hours tostabilize the film. Throughout the coating process, product temperatureof 30-35° C. was maintained. The spray rate range was between 5-15g/min. The Cured pellets were then blended with Avicel PH 102 and AvicelPH 200 for about 10 minutes using a suitable blender. The Magnesiumstearate was added to the blender and blended for 5 minutes. The finalblend was compress at 766 mg tablet weight and hardness of 8-16 kp. TheCompressed tablets were then loaded into the conventional coating panfor color coating.

Example 31

Expansion layer Mannitol  70 mg Microcrystalline Cellulose  50 mgCarbopol 71G 128 mg Hydroxypropyl Methylcellulose, type 2910 128 mg(METHOCEL ™ K4M CR) Croscarmellose sodium  20 mg (AC-DI-SOL ®) MagnesiumStearate  4 mg

Barrier layer EUDRAGIT ® NE 30D solids 97.3 mg Calcium Stearate 16.2 mgSimethicone Emulsion  0.2 mg Purified water —

Diffusion layer Oxycodone Hydrochloride   40 mg EUDRAGIT ® NE 30D solids89.2 mg Aerosil ® 200   2 mg Tween ® 80   2 mg Purified water —

Color coat Opadry 85F18422 Powder 30 mg Purified Water —

This formulation with respect to oxycodone was tested by comparing therelease rate of a tablet made according to Example 31 when takenproperly (intact) as compared to a ground form of the same tabletformulation. The results are reported in FIG. 1 and show that most ofthe medication is released to the patient when the tablet is properlytaken.

Tablets comprising the pharmaceutical composition of Example 31 were cutinto 2 and 8 pieces using a sharp device such as a knife and scissors.The expansion layer powder was completely removed. FIG. 4 shows thecomparison of such rate. This demonstrates that when the tablets of thecurrent invention are physically compromised, the physical bond betweenthe diffusion layer and the barrier layer is substantially preserved.The relative surface area of the diffusion layer increases onlymarginally, preventing a significant increase in the drug release.Therefore, in some embodiments, even when the dosage form containing thepharmaceutical composition of the invention is physically compromised,the drug substance maintains essentially the same release profile, ascompared to an intact dosage form.

1. An oral, extended release pharmaceutical composition, comprising: abarrier layer, comprising a first polymer, and a diffusion layer,comprising a second polymer, substantially covering the barrier layer,wherein the diffusion layer is bonded to the barrier layer and comprisesa drug that is substantially homogeneously distributed within the secondpolymer and diffuses from the diffusion layer within thegastrointestinal (GI) tract, wherein the drug comprises hydromorphone ora pharmaceutically acceptable salt thereof.
 2. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition furthercomprises an expansion layer comprising an expandable polymer, andwherein the barrier layer substantially covers the expansion layer. 3.The pharmaceutical composition of claim 2, wherein the expansion layercomprises a polymer present in the range of 5 to 90% by weight based onthe total weight of the dosage form.
 4. The pharmaceutical compositionof claim 2, wherein the pharmaceutical composition is configured suchthat when the pharmaceutical composition is physically compromised andparticles of the pharmaceutical composition containing the expansionlayer are formed and exposed to a liquid, the expandable polymer of theexpandable layer absorbs at least a portion of the liquid.
 5. Thepharmaceutical composition of claim 1, wherein the diffusion layer isphysically bonded to the barrier layer.
 6. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition isconfigured such that when the pharmaceutical composition is administeredin an intact form, the first polymer of the barrier layer issubstantially undissolved in the GI tract.
 7. The pharmaceuticalcomposition of claim 1, wherein the second polymer of the diffusionlayer provides a timed release of drug over a period of about 6 to about24 hours.
 8. The pharmaceutical composition of claim 1, wherein thepharmaceutical composition is configured such that when thepharmaceutical composition is physically compromised and particles ofthe pharmaceutical composition containing the diffusion layer and thebarrier layer are formed, the bond between the diffusion layer andbarrier layer within the particles is substantially preserved.
 9. Thepharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition is configured such that when the pharmaceutical compositionis administered in physically compromised form to a subject, the Cmaxand/or AUC achieved after a time period selected from the groupconsisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48hours after administration is substantially the same or lower than theCmax and/or AUC achieved when the pharmaceutical composition isadministered in an intact form.
 10. The pharmaceutical composition ofclaim 9, wherein the pharmaceutical composition is configured such thatthe Cmax and/or AUC achieved after a time period selected from the groupconsisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48hours after administration, is 20-75% lower than the Cmax and/or AUCachieved when the pharmaceutical composition is administered to asubject in an intact form.
 11. The pharmaceutical composition of claim1, wherein the pharmaceutical composition comprises an additionalrelease layer, wherein the additional release layer is an immediaterelease layer substantially covering the diffusion layer, wherein theadditional release layer comprises at least one additional drug.
 12. Thepharmaceutical composition of claim 11, wherein the at least oneadditional drug in the additional release layer is selected from thegroup consisting of acetaminophen and nonsteroidal anti-inflammatorydrugs.
 13. An oral, extended release pharmaceutical composition,comprising a drug in a pharmaceutically effective amount, wherein thepharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the Cmax/AUC achieved after administration is lowerthan the Cmax/AUC achieved after a time period selected from the groupconsisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48hours after administration, of a physically compromised bioequivalentcomposition not comprising means for deterring abuse, wherein the drugcomprises hydromorphone or a pharmaceutically acceptable salt thereof.14. An oral, extended release pharmaceutical composition, comprising adrug in a pharmaceutically effective amount, wherein the pharmaceuticalcomposition is configured such that when the pharmaceutical compositionis administered in physically compromised form to a subject, the Cmaxand/or AUC achieved after administration is lower than the Cmax and/orAUC achieved after a time period selected from the group consisting of 2hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48 hours afteradministration, of a bioequivalent composition not comprising means fordeterring abuse, wherein the drug comprises hydromorphone or apharmaceutically acceptable salt thereof.
 15. An oral, extended releasepharmaceutical composition, comprising a drug in a pharmaceuticallyeffective amount, wherein the pharmaceutical composition in configuredsuch that when the pharmaceutical composition is administered inphysically compromised form to a subject, the rate of drug released fromthe composition within a time period selected from the group consistingof 2 hours, 4 hours, 8 hours, and 16 hours, is substantially the same orlower than the rate of drug released when the pharmaceutical compositionis administered in an intact form, wherein the drug compriseshydromorphone or a pharmaceutically acceptable salt thereof.
 16. Anoral, extended release pharmaceutical composition, comprising a drug ina pharmaceutically effective amount, wherein the pharmaceuticalcomposition in configured such that when the pharmaceutical compositionis administered in physically compromised form to a subject, the amountof drug released from the composition within a time period selected fromthe group consisting of 2 hours, 4 hours, 8 hours, and 16 hours, issubstantially the same or lower than the amount of drug released whenthe pharmaceutical composition is administered in an intact form,wherein the drug comprises hydromorphone or a pharmaceuticallyacceptable salt thereof.
 17. The pharmaceutical composition of claim 16,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in physically compromisedform to a subject, the amount of drug released from the compositionwithin a time period selected from the group consisting of 2 hours, 4hours, 8 hours, and 16 hours, is no more than 75% of the amount of drugreleased when the pharmaceutical composition is administered in anintact form.
 18. An oral, extended release pharmaceutical composition,comprising a drug in a pharmaceutically effective amount, wherein thepharmaceutical composition in configured such that when thepharmaceutical composition is contacted with an alcohol or consumed withan alcohol, the rate of drug released from the composition within a timeperiod selected from the group consisting of 2 hours, 4 hours, 8 hours,and 16 hours, is substantially the same or lower than the rate of drugreleased when the pharmaceutical composition is administered without analcohol, wherein the drug comprises hydromorphone or a pharmaceuticallyacceptable salt thereof.
 19. An oral, extended release pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least50% of the amount of drug is released after 8 hours and when thepharmaceutical composition is administered in physically compromisedform no more than 40% of the amount of drug is released after 1 hour,wherein the drug comprises hydromorphone or a pharmaceuticallyacceptable salt thereof.
 20. The pharmaceutical composition of claim 19,wherein when the pharmaceutical composition is administered inphysically compromised form no more than 35% of the amount of drug isreleased after 15 minutes.
 21. An oral, extended release pharmaceuticalcomposition, comprising a drug in a pharmaceutically effective amount,wherein the pharmaceutical composition is configured such that when thepharmaceutical composition is administered in an intact form at least90% of the amount of drug is released after 1 hour and when thepharmaceutical composition is administered in physically compromisedform no more than 75% of the amount of drug is released after 1 hour,wherein the drug comprises hydromorphone or a pharmaceuticallyacceptable salt thereof.
 22. The pharmaceutical composition of claim 1,wherein the pharmaceutical composition is in a pharmaceutical dosageform selected from the group consisting of a tablet, a capsule, a microtablet, granules, pellets, a lozenge, a lollipop, and a coated capsule.23. The pharmaceutical composition of claim 22, wherein thepharmaceutical dosage form is a tablet.
 24. The pharmaceuticalcomposition of claim 1, wherein the composition comprises hydromorphoneor a pharmaceutically acceptable salt thereof in an amount of about 1 mgto about 64 mg.
 25. A method of making an abuse resistant oral, extendedrelease pharmaceutical composition, comprising: forming a barrier layer,wherein the barrier layer comprises a first polymer; applying adiffusion layer over the barrier layer to substantially cover thebarrier layer, wherein the diffusion layer comprises a second polymerand a drug that is homogeneously distributed within the second polymer;and bonding the diffusion layer to the barrier layer, wherein the drugcomprises hydromorphone or a pharmaceutically acceptable salt thereof.26. The method of claim 25, wherein the bonding of the diffusion layerto the barrier layer is a physical bonding.
 27. A method of making anabuse resistant oral, extended release pharmaceutical composition,comprising: forming an expansion layer comprising an expandable polymer;applying a barrier layer over the expansion layer to substantially coverthe expansion layer, wherein the barrier layer comprises a firstpolymer; applying a diffusion layer over the barrier layer tosubstantially cover the barrier layer, wherein the diffusion layercomprises a second polymer and a drug that is homogeneously distributedwithin the second polymer; and bonding the diffusion layer to thebarrier layer, wherein the drug comprises hydromorphone or apharmaceutically acceptable salt thereof.
 28. The method of claim 27,wherein the bonding of the diffusion layer to the barrier layer is aphysical bonding.
 29. The method of claim 27, comprising applying thebarrier layer onto the expansion layer by spraying or dry coating.
 30. Amethod of treating a condition, comprising administering to a patient inneed thereof the pharmaceutical composition of claim
 1. 31. An oral,extended release pharmaceutical composition, comprising a drug in apharmaceutically effective amount, wherein the pharmaceuticalcomposition is configured such that when the pharmaceutical compositionis administered in physically compromised form to a subject, theintensity of the euphoria is substantially the same or lower than theintensity of the euphoria achieved after administration of a physicallycompromised bioequivalent composition not comprising means for deterringabuse, wherein the drug comprises hydromorphone or a pharmaceuticallyacceptable salt thereof.